Abstract 5445: New discovery and development of transglutaminase 2 inhibitor
Authors: Eun Yi Cho, Hyeon Joo Kim, Byeonghak Moon, Yerin Jo, Jinsu Bae, Ga Ram Kim, Yong-Chul Kim, Sun Kyoung Kang, Woo Sun Kwon, Tae Soo Kim, Sun Young Rha, Hyun Cheol Chung
Journal: Cancer Research (2022)

Abstract Transglutaminase 2 (TGase 2) is a multi-functional, ubiquitous enzyme that is important for various cellular processes, including apoptosis, development, differentiation, wound healing, and angiogenesis. TGase2 plays important roles in the pathogenesis of many diseases, including cancers, autoimmune pathologies, neurodegeneration, and Inflammation. Dysregulation of TGase 2 expression can both activate pathogenesis and aggravate disease state. TG2 is overexpressed in cancers such as renal cell carcinoma (RCC), pancreatic, triple negative breast (TNBC) and, gastric cancer, and is associated with poor prognosis. It is also involved in drug resistance and cancer cell metastasis. These evidences provide the rationale for the development of TGase2 inhibitors as novel anticancer agents. We selected TGase2 inhibitors from a library of compounds, validated and optimized a final compound. An optimized compound was synthesized by modifying aromatic substitution, various alkyl groups, and PK improvement in consideration of activity and physical properties and named as MD102. The IC50 value of TGase2 activity inhibition of MD102 is 100-400 nM similar to positive control of streptonigrin and IC50 of cell growth inhibition was 1~10 μM in TGase2 overexpressing RCC, TNBC and gastric cancer cell lines. The cell growth inhibitory dose of MD102 was depend on the expression level of TGase2. We observed MD102 inhibited cell growth through suppression of PI3K/AKT pathway (AKT, p-AKT, mTOR, p-mTOR). Also, MD102 has inhibited the growth of endothelial cell (HMVEC) with IC50 of 1.2nM and tube formation of HUVEC with 35%, suggesting antiangiogenic effect. The angiogenesis was inhibited by suppression of NFkB pathway including p50, p65, HIF1-a, and VEGF. Oral administration of MD102 once daily for 4 weeks showed significant tumor growth inhibition of 50% at 50mg/kg compare to control group in both xenograft models of the ACHN (RCC) and MDA-MB231 (TNBC) cell lines. And as a preliminary toxicity test, oral administration of MD102 up to 2000mg/kg for 3 weeks did not show deaths or any adverse reactions in body weight and laboratory tests of blood counts, liver and renal functions. MD102, a TGase2 inhibitor, is expected to be a potential candidate in TGase2-overexpressing cancers, including RCC and TNBC, as it shows antitumor activity without serious toxicity, although further validation is required. In addition, it is expected that area expansion to many diseases induced by TGase2 pathogenesis Citation Format: Eun Yi Cho, Hyeon Joo Kim, Byeonghak Moon, Yerin Jo, Jinsu Bae, Ga Ram Kim, Yong-Chul Kim, Sun Kyoung Kang, Woo Sun Kwon, Tae Soo Kim, Sun Young Rha, Hyun Cheol Chung. New discovery and development of transglutaminase 2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5445.